This research proposes to investigate our interesting findings of high scientific and medical significance involving colonic malignancies that are common and deadly in human patients. In humans, inflammation is a well-recognized risk factor for cancer. We have shown in mice that supplementation with anti-inflammatory CD4+ regulatory cells (Treg) which promote immune homeostasis in the lower bowel are highly effective in preventing and treating colonic cancers. However, high levels of inflammatory factors within the tumor microenvironment may create a vicious cycle that undermines protective functions of Treg. Thus, strategies that enhance potency of Treg to maintain homeostasis and constructively down-regulate inflammation may be of great value in fighting cancer. A recent and repeatable finding in our lab relates to the well-regarded 'hygiene hypothesis'in that prior exposures to enteric bacteria appear to enhance potency of Treg to protect against cancer. We propose to test immune strategies that optimize the intestinal balance between bacteria, inflammatory cytokines and Treg. We speculate that targeted stimulation of beneficial Treg using oral vaccination strategies may ultimately provide population-based approaches to abolish inflammation-associated cancers in humans. PUBLIC HEALTH RELEVANCE: Chronic inflammation increases risk of cancer in humans and in mice. Anti-inflammatory regulatory T cells (Treg) normally function to maintain immune balance and down- regulate inflammatory factors that lead to cancer growth. We propose to build upon our recent scientific breakthroughs and test strategies in mice that will stimulate potent and highly beneficial Treg to prevent cancer and impart healthful longevity in humans.